The development of sophisticated pharmaceutical products and drug delivery methods that can provide precise targeting, timing and dosing of therapeutic drugs has been necessitated in part by complex requirements in the treatment of organ-specific disorders due to diseases such as cancer, HIV/AIDS, cystic fibrosis, etc. Some of the contributing factors to the complex requirements of treatment include the toxicity of drugs used in the treatment of such diseases, limited therapeutic activity of the drugs, as well as the inaccessibility and heterogeneity of the diseased organ.
Progress has been made in the delivery of drugs, particularly in the development of drug carriers showing low toxicity and which are capable of providing improved targeting of the diseased cells. Several types of drug carriers that provide improved drug delivery have been investigated, including liposomes, drug-polymer conjugates and nanoparticles.
Polymeric core-shell nanoparticles have emerged recently as promising colloidal carriers for targeting poorly water-soluble and amphiphilic drugs as well as genes to tumour sites [Kataoka et al.—Advanced Drug Delivery Rev. 47 (2001) 113-131; V. P. Torchilin—J. Control. Rel. 73 (2001) 137-172; Allen et al.—Cool. Surf. B: Biointerfaces 16 (1999) 3-27]. Polymeric core-shell nanoparticles are small in size, generally less than 200 nm, and can solubilize hydrophobic drugs, genes or proteins in their inner cores through hydrophobic interaction, electrostatic interaction and hydrogen bonding etc., while exposing their hydrophilic shells to the external environment. This effectively protects the enclosed bioactive compounds against degradation and enables them to exhibit prolonged activity in the systemic circulation by avoiding being scavenged by reticuloendothelial systems (RES). With polymeric core-shell nanoparticles, targeting can be achieved, both passively and actively, —through an enhanced permeation and retention effect (EPR effect) [Matsumura et al.—Cancer Research 46 (1986) 6387-6392] and the incorporation of recognition signals onto the surface of the micelles [Kabanov et al.—FEBS Lett. 258 (1989) 343-345] or introducing a polymer sensitive to variations in physiological environment such as temperature or pH.
Polymeric nanoparticles which have shells constructed from temperature-sensitive poly(N-isopropylacrylamide) (PNIPAAm) have recently attracted considerable attention because of the polymer's thermal responsiveness. PNIPAAm exhibits a lower critical solution temperature (LCST) of around 32° C. in aqueous solution, below which the polymer is water-soluble and above which the polymer is water-insoluble [Taylor et al.—J. Polym. Sci.: Polym. Chem. Ed. 13 (1975) 2551-2570]. The temperature-sensitivity of the polymer advantageously provides a means to target drug carriers thermally.
Okano et al. reported the synthesis of adriamycin-incorporated micellar structures derived from PNIPAAm-b-poly(butylmethacrylate) and PNIPAAm-b-poly(D,L-lactide) block copolymers [Chung et al.—J. Control. Rel. 62 (1999) 115-127; Kohori et al—Colloids and Surfaces B: Biointerfaces 16 (1999) 195-205]. The core-shell nanoparticles were well formed below LCST, but deformed at temperatures higher than LCST. The release of the drug was regulated through a combination of local heating and cooling cycles. However, it was found that temperature regulation alone was not efficient in targeting deep tissues or tumours.
One alternative to temperature sensitive drug carriers are pH-sensitive drug carriers. It is known, for example, that the extracellular pH of most solid tumours range from 5.7 to 7.8 [Vaupel et al.—Cancer Research 41 (1981) 2008-2013], while the pH of the tumour interstitial fluid rarely declines below pH 6.5. It is a challenge to provide a drug carrier with such a narrow pH window [Drummond et al.—Progress in Lipid Research 39 (2000) 409-460].
Chen and Hoffman reported the synthesis of a copolymer of NIPAAm and acrylic acid and its pH-dependent LCST, and proposed its possible application in drug targeting [Nature 373 (1995) 49-52]. More recently, core-shell nanoparticles made from poly(L-histidine)-b-poly(ethylene glycol) (PEG) were reported to be pH-sensitive, which released the enclosed drug, doxorubicin (DOX), at pH from 7.4 to 6.8 [Lee et al.—J. Control. Rel. 90 (2003) 363-374; J. Control. Rel. 91 (2003) 103-113]. The acidic environment triggered the destabilization of the core-shell nanoparticles and thus release the enclosed drug molecules at tumour tissues.
WO 01/87227 A2 discloses the use of a colloidal composition consisting of polymeric micelles having a hydrophobic core and a hydrophilic shell. The pH- and temperature-sensitive micelles are derived from a copolymer of NIPAAm, methacrylic acid and octadecyl acrylate. The temperature-sensitive and pH-sensitive moieties are located on the shell of micelles.
Despite the developments that have taken place, limitations in the current drug carriers still exist for which continuing efforts are needed to improve their performance.
Accordingly, it is an object of the present invention to provide polymeric compounds which can be used as drug carriers that have improved pH and temperature sensitivity, and thus provide improved drug delivery performance.